Microbial Conditioning of the
Mucosal Immune System
Silbart Lecture – 2/19/14
Pathogens/toxins often
enter our bodies across
mucosal surfaces
Surface Areas:
Skin – 2 m2
Lung – 140 m2
G.I. – 200 m2
Thus, a very large
commitment of
lymphocytes
is needed to protect
these surfaces
Nature Reviews Immunology
Nagler-Anderson Vol 1: 59-67 (2003)
Innate and antibody-mediated mucosal host
defense mechanisms. Shown are soluble
antimicrobial proteins lactoperoxidase,
lactoferrin, and lysozyme, and the peptide
defensins. Human neutrophil peptide (HNP)
and Paneth cells in crypt regions produce adefensins, whereas epithelial cells secrete bdefensins.
Anti-microbial peptides (AMPs)
© 2003 by LIPPINCOTT WILLIAMS & WILKINS
Fundamental Immunology
Tight junctions
maintain mucosal
integrity
Fundamentals of Mucosal
Immunology
Presence of foreign antigens at a mucosal surface is
generally not sufficient to elicit a mucosal immune
response - in fact, in the absence of “signal 1 danger” Ag is often toleragenic (e.g. non-replicating
protein antigens).
Regulation of mucosal immune responses is distinct
from systemic “humoral” immunity
Stimulation at one mucosal surface often results in
mucosal immunity at many, if not all mucosae “CMIS”
The “Common Mucosal Immune System”
“D-MALT”
“O-MALT”
Cross section of a Peyer’s
Patch; epithelial cells (blue)
T cells (red) B cells (green)
Separate Inductive and
Effector Sites
Antigen uptake occurs at the “follicle associated
epithelium” (FAE), a lymphoepithelial structure that
has few if any goblet cells (thereby less mucus) and
specialized epithelial cells known as “M” cells.
M cells sample the intestinal surface and lumen
through phagocytosis, then pass antigens into a
sub-epithelial pocket without processing.
Note: Many pathogens exploit Peyer’s patches - e.g. Salmonella sp.
Fagarasan and Honjo; Nature Reviews Immunology: 3: 63-72 (2003)
Nature Reviews
Immunology
Nagler-Anderson
Vol 1: 59-67 (2003)
Entry of GFPlabeled Salmonella
typhimurium through
the FAE, and uptake
by CD11c+ DCs
(DC’s – red, bacteria
green)
Nature Reviews Immunology
Nagler-Anderson Vol 1: 59-67 (2003)
The Germinal Center
Microenvironment
In the dome region of a Peyer’s patch,
the T helper cell population is heavily
biased toward a Th2 response.
This leads to B cell isotype switching
from sIgM+/sIgD+ to sIgA, heavily
influenced by TGF-beta and IL-5.
Activation induced
cytidine deaminase
Fagarasan and Honjo; Nature
Reviews Immunology: 3: 63-72 (2003)
Reciprocal
down-regulation
Lymphocyte trafficking
Antigen-specific, IgA-committed lymphoblasts
emigrate from the FAE, lodge transiently in
the mesenteric lymph nodes, where antigen
re-exposure and secondary rounds of
proliferation/differentiation can occur.
These cells rejoin circulation via the thoracic
duct, then home to effector tissues, generally
the lamina propria of the intestine or lung, or
a variety of glandular tissues.
Kunkel and Butcher
Nature Reviews
Immunology
3: 822-829 (2003)
Selectins and integrins
bind to tissue specific
cellular addressins (like
zip codes).
Brandtzaeg et al. Immunology
Today: 20:267-277 (1999)
Differential
lymphocyte
trafficking
Brandtzaeg et al. Immunology
Today: 20:267-277 (1999)
Kunkel and Butcher; Nature Reviews Immunology
3: 822-829 (2003)
Secretory IgA Production
Once the IgA-committed lymphoblasts extravasate
into the lamina propria, they will proliferate in the
presence of antigen, then terminally differentiate
into an S-IgA secreting plasma cell.
S-IgA dimers, joined by a “J” chain, bind to the
polymeric immunoglobulin receptor (pIgR), and SIgA is expelled into the lumen with the secretory
component attached.
Note: S-IgA is substantially more proteolytically stable than IgG
Trans-epithelial
transport of
dimeric IgA
© 2003 by LIPPINCOTT WILLIAMS & WILKINS
Fundamental Immunology
Secretory component derived
from pIgR (22% sugar)
Molecular dimensions, proteolytic fragments, and domain structure of the human
dimeric secretory immunoglobulin A1 molecule.
© 2003 by LIPPINCOTT WILLIAMS & WILKINS
Fundamental Immunology
The Nasal Associated
Lymphoid Tissues (NALT)
Recognition of commensals and pathogens - TLRs
Basolateral expression
Defects in NOD2 are
found in 30% of Crohn’s
disease patients
Tolerance
Mediated by encounter with antigen
while T cells are immature, usually
within the thymic epithelium
Secondary mechanisms for peripheral
tolerance through anergy or apoptosis.
“high-zone” tolerance occurs following
activation induce apoptosis.
Tolerance is a dynamic process, and
depends on dose, timing, route of
infection and localization of antigen.
Th0
www.scielo.br/scielo.php?pid=S0100-879X200900...
Also Tr1 and Th3
Artis, 2008
1014
Artis, 2008
Artis, 2008
Artis, 2008
Commensals required for
proper development as neonates
Premature birth
C-sections
Antibiotic use
C. diff necrotizing
enterocolitis (NEC)
[colonization resistance]
Bifidobacter and
Lactobacillus love
breastmilk oligo-saccharides
Intestinal dysbiosis, pre-biotics and probiotics
Prebiotics are non-digestible carbohydrates, such as oligosaccharides and fructo-oligosaccharides.
They remain in the digestive tract where they stimulate the growth of beneficial bacteria.
http://nutrition.about.com/od/therapeuticnutrition1/p/pro_prebiotics.htm